The present invention relates in general to ellipticine-like chemicals which have been shown to have schistosomicidal and antitumor effects, and in particular 9-substituted 5-hydroxymethyl-11-methyl-6H-pyrido [4,3-b] carbazole N-alkyl or aryl carbamates.
A great deal of interest has been shown in the alkaloids ellipticine (1; 5,11-dimethyl-6H-pyrido [4,3-b] carbazole) and its regioisomer olivacine (2; 1,5-dimethyl-6H-pyrido [4, 3-b] carbazole) because of their antitumor properties in animals and humans. Ellipticine has been shown to react with DNA by an intercalation process which may account for its cytotoxicity. It has also been found that 1 markedly inhibited DNA polymerase but not RNA polymerase. At concentrations of 0.2 and 1.0 micrograms/mL, the drug inhibited DNA and RNA synthesis as measured by the incorporation of [.sup.3 H]thymidine and [.sup.3 H]uridine. At these concentrations there was little effect on protein synthesis. It was concluded that inhibition of nucleic acid synthesis was an important contribution to the cytotoxic effect of ellipticine. See: Suffness, M.; Cardell, G.A. The Alkaloids; Brossi, A., Ed.; Academic: New York, 1985; Vol. XXV; LePecq, J-B.; Dat Xoung, N.; Gosse, C.; Paoletti, C. Proc. Natl. Acad. Sci. U.S.A. 1974, 71, 5078. Maftouh, M.; Besselievre, Monserrat, B.; Lesca, P.; Meunier, B.; Husson, H.P.; Paoletti, C. J. Med. Chem. 1985, 28, 708; and Li, L.M.; Cowie, C.H. Biochem. Biophys. Acta 1974, 353, 3751.
One author (Sethi, V.S. Biochem. Pharmacol. 1981, 30, 2026) was able to show that 1 did inhibit RNA polymerase but at concentrations far higher than those of other antitumor agents such as dactinomycin, adriamycin, and daunomycin. ##STR2##
Compound 3 was found to produce DNA double and single strand breaks in L1210 cells exposed to the drug, and that this compound was a more active antitumor agent than 1. Compounds 2 and 4 were also found to be active antitumor agents in vivo. Compound 6 was found to be cytotoxic. Compound 7 was found to be inactive in vivo against murine L1210 leukemia. Compound 5 was also found to be inactive.
In other studies on the mode of antischistosomal and antitumor action of lucanthone (8) and hycanthone (9) and its cogeners, evidence was found that the methyl group of lucanthone (8) is metabolized in the mammalian host to hycanthone (9), which then may be enzymically esterified to either 10 or 11. These may dissociate nonenzymically to the carbonium ion 12, which alkylates DNA to form the adduct 13. The carbamate ester 14 acted as a surrogate for 10 or 11. The enhanced antitumor action of 15, in which the 7-OH is regiochemically analogous to the 9-OH in 6, was attributed to stronger intercalation into DNA as compared with hycanthone. See: Archer, S.; Yarinsky, A. Prog. Drug. Res. 1972, 16, 12; Cioli, D.; Pica-Mattoccia, L.; Rosenburg, S.; Archer, S. Life Sci. 1985, 37, 161; Archer, S.; Zayed, A. H; Rej, R.; Rugino, T.A. J. Med. Chem. 1983, 26, 1240; and U.S. Pat. No. 4,539,412 to Archer. ##STR3##
In view of the foregoing results, the role of the methyl groups in the ellipticine series is believed to be very important. One hypothesis to rationalize the lack of activity of compound 5 is that the lack of a C-5 methyl group does not permit the metabolic conversion of a hydroxymethyl group, which on enzymic esterification would be converted to an alkylating agent similar to compounds 10 and 11.